Physiological responses of extrathymic T cells in the liver

The liver has been found to be one of the important hematopoietic organs even after birth. Namely, adult liver still comprises c-kit+ stem cells and gives rise to extrathymic T cells, natural killer (NK) cells, and even granulocytes. Extrathymic T cells generated in the liver of mice are intermediate T-cell receptor (TCR(int)) cells, including the NK1.1+TCR(int) (i.e. NKT cells) and NK1.1-TCR(int) subsets. Although extrathymic T cells are few in number in youth, they gradually increase in number with aging. Even in youth, the number and function of extrathymic T cells are elevated under conditions of stress, infection, malignancy, pregnancy, autoimmune disease, chronic graft-versus-host diseases, etc. Under these conditions, the mainstream of T-cell differentiation in the thymus, which produces conventional T cells, is rather suppressed. Since extrathymic T cells comprise self-reactive forbidden clones and mediate cytotoxicity against abnormal self-cells (e.g. malignant tumor cells, microbially infected hepatocytes, and regenerating hepatocytes), they are beneficial for the elimination of such cells. However, overactivation or continuous activation of extrathymic T cells might be harmful and responsible for the onset of autoimmune diseases. We finally propose the possibility that switching of the immune system from the thymus to the liver might be regulated by the autonomic nervous system as well as by cytokines.